PROJECT SUMMARY In 90% of cases, healthy persons infected with Mycobacterium tuberculosis (Mtb) remain asymptomatic. This implies that the host generates and maintains a partially protective immune response capable of containing bacterial replication. When this equilibrium is altered, such as during HIV-associated CD4 T cell depletion, TB disease can occur. However, the precise nature of Mtb-specific CD4+ T cells that confer immune protection remains elusive, hindering the development of new vaccines. It is now clearly established that while necessary, IFN? is not sufficient to provide lung protection to Mtb. The recent finding, in a mouse model, that the TNF superfamily molecule CD153 confers partial protection for pulmonary Mtb infection (in an IFN?- independent manner) reveals a new avenue to potentially identify an important immune correlate of protection to Mtb in humans. In ongoing experiments, we have found that Mtb-specific CD4+ T cells from individuals with latent TB infection (LTBI) express CD153 and that the expression of this molecule was significantly reduced in patients with active TB disease. Additionally, in TB asymptomatic persons with evidence of TB related lung inflammation measured using PET/CT, CD153 expression in Mtb-specific CD4 T cells negatively associates with lung metabolic activity. These findings strongly suggest that CD153, along with IFNg, may be required to confer optimal protection against pulmonary Mtb infection in humans. To better understand the role of CD153 (and its receptor, CD30) for Mtb protection, we will: 1) comprehensively characterize Mtb-specific CD153+ CD4 T cells during latent and active TB, both in peripheral blood and at sites of TB diseases; 2) define the impact of HIV infection on Mtb-specific CD4 T cells expressing CD153 and 3) investigate the mechanisms of action of the CD153/CD30 pathway in response to Mtb. This study will 1) enhance our understanding of immune mechanisms required for human TB protection and 2) identify novel mechanisms by which HIV infection alters these immune responses. This project could lead to the development of new tools to monitor the efficacy of novel TB vaccines.